ORATANE Soft capsule Ref.[50314] Active ingredients: Isotretinoin

Absorption

There is considerable inter-individual variation in the bioavailability of oral isotretinoin. After oral administration of 80 mg (2 × 40 mg capsules) given in the fasting state peak plasma concentrations ranged from 167 to 459 nanogram/mL and mean time to peak was 3.2 hours in healthy volunteers, while in acne patients peak concentrations ranged from 98 to 535 nanogram/mL (mean 262 nanogram/mL) with a mean time to peak of 2.9 hours.

Taking isotretinoin with food increases bioavailability up to 1 ½ to 2 times greater than when taken in fasting conditions.

Distribution

Isotretinoin is extensively bound to plasma proteins (99.9%). Albumin appears to be the major binding protein.

Tissue Distribution in Animals: Tissue distribution of ¹⁴C- isotretinoin in rats revealed high concentrations of radioactivity in many tissues after 15 minutes, with a maximum in 1 hour, and declining to non-detectable levels by 24 hours in most tissues. After seven days, however, low levels of radioactivity were detected in the liver, ureter, adrenal, ovary and lacrimal gland.

Biotransformation

Three metabolites have been identified in plasma: 4-oxo-isotretinoin, tretinoin (all-trans retinoic acid), and 4-oxo-tretinoin. The major blood metabolite of isotretinoin is 4-oxo-isotretinoin. After two 40 mg capsules of isotretinoin, maximum concentrations of the metabolite of 87 to 399 nanogram/mL occurred at 6 to 20 hours. The blood concentration of the major metabolite generally exceeded that of isotretinoin after 6 hours.

The mean +SD minimum steady-state blood concentrations of isotretinoin were 160 +19 nanogram/mL in 10 patients receiving 40 mg twice daily. After single and multiple doses, the mean ratio of areas under the curves of isotretinoin to 4-oxo-isotretinoin is 3 to 3.5.

Elimination

The terminal elimination half-life of isotretinoin ranged from 10 to 20 hours in volunteers and patients. Following an 80 mg liquid suspension oral dose of ¹⁴C-isotretinoin, ¹⁴C-activity in blood declined with a half-life of 90 hours. Relatively equal amounts of radioactivity were recovered in the urine and faeces with 65-83% of the dose recovered. The apparent half-life for elimination of the 4-oxo-metabolite ranged from 11 to 50 hours with a mean of 29 hours. This metabolite is subject to recycling in the enterohepatic circulation.

In the reproductive studies in rats (2, 8 or 32 mg/kg/day; 2-generation), no adverse effects were noted on gonadal function, fertility, gestation or neonatal viability, although the average weight in the high dose group was slightly reduced.

In dogs, testicular atrophy was noted after treatment with isotretinoin for approximately 30 weeks at dosages of 60 or 20 mg/kg/day. In general, there was microscopic evidence for appreciable depression of spermatogenesis but some sperm were observed in all testes examined and in no instance were completely atrophic tubules seen.

Carcinogenicity

In Fischer 344 rats given isotretinoin at dosages of 32 or 8 mg/kg/day for greater than 18 months, there was dose-related increased incidence of pheochromocytoma. The incidence of adrenal medullary hyperplasia was also increased at the higher dosage. There is doubt as to the validity of this animal model as a predictor of tumorigenicity in man, as the Fischer rat is genetically predisposed to the Multiple Endocrine Neoplasia Syndrome which includes spontaneous occurrence of pheochromocytoma. In these studies, there was also a dose-related decrease in the incidence of liver adenomata, liver angiomata and leukemia.

Teratogenicity

Isotretinoin is teratogenic in rats and rabbits although sensitivity differs. In the rat, doses up to 50 mg/kg/day were not teratogenic but 150 mg/kg/day was teratogenic. At lower doses in the rat perinatal and post-natal studies (5, 15 and 32 mg/kg/day) increased pup mortality was noted in all treatment groups. This was attributed to a dose-related reduction in maternal food intake. Body weight development of pups was significantly impaired in the high dose groups.

In the rabbit, a dose of 10 mg/kg/day caused abortions in 9 out of 13 animals and teratogenicity and embryotoxicity were observed in the remaining 4 litters.

Genotoxicity

Isotretinoin was negative in tests for gene mutation (histidine reversion in S. typhimurium), chromosomal damage in vitro (Chinese hamster lung cell and S. cervisiae D7 assays) and in vivo (Mouse micronucleus test), and unscheduled DNA synthesis in vitro (rat hepatocytes).